Dr. Minh Dinh is a junior faculty researcher at Northwestern University, a leading institution in HIV research. The institution fully supports her research endeavors with extensive resources available to her in the Hope and Wolinksy labs, as well as other areas on campus. Her mentor is Dr. Thomas Hope, a well-published researcher in HIV pathogenesis and transmission. Dr. Hope's mentorship and expertise will greatly enhance her research efforts in the upcoming years. Dr. Dinh plans to maintain a career in academic medicine in the field of HIV transmission and prevention research. She will nurture the development of her early career at Northwestern with continued graduate studies in virology and biology, and regular meetings and conferences in the fields of virology and infectious diseases. Her work in the Hope lab has been highly productive to date, and holds promise for a successful career in HIV research. Several randomized control clinical trials have demonstrated the protective benefit of male circumcision in reducing the risk of HIV acquisition in men. The primary objective of my research plan is to gain insight into the biologic mechanism behind this protective effect. Our lab has developed strategies to visualize various aspects of HIV activity and have successfully used these methods to study HIV transmission in tissue. Using immunofluorescence microscopy, I will study adult human penile epithelium from circumcised and uncircumcised cadaveric specimens. I will first characterize structural and cellular components to determine differences between tissues from these two groups. Using ex vivo tissue explant cultures, I will also investigate early interactions between photactivatable HIV GFP-Vpr viral particles and male genital tissue, including how the particles move through the epithelia. Long-term explant cultures will allow me to visualize target cells such as Langerhans and CD4+ T-cell lymphocytes that have been successfully infected by HIV. My hypothesis is that HIV more easily penetrates and infects underlying target cells in foreskin tissue and uncircumcised penile tissue, leading to increased rates of HIV infection in uncircumcised men. In collaboration with the HIV Vaccine Trials Network, I will examine structural and cellular features in and photoactivatable HIV with foreskin tissue obtained from Merck Ad5-HIV-1 vaccine trial participants to determine the vaccine's effect on these areas. I predict that the vaccine and pre-existing HSV infections increased localized target cell recruitment that led to higher HIV infection risks upon exposure to the virus. My next aim is to study HIV sexual transmission using the male rhesus macaque model. Macaque models have allowed us to confirm findings from human female cervical explant cultures and these experiments with male macaques will similarly be crucial to our studies. I will have short-term access to retired animals from other Tulane studies, along with 10 circumcised macaques acquired for a separate study. Skin barrier function will be assessed using transepidermal water loss measurements. Circumcised and uncircumcised male macaque genitalia will be inoculated with photoactivatable HIV-1 to study initial interactions in a living model. Tissue will be studied for target cells, keratin, and intercellular junctions. Long-term tissue explants inoculated with SIV GFP-Vpx constructs will be used to study early SIV infected cells. Altogether, these high impact studies will help us to better understand how male circumcision effects HIV transmission in men. PUBLIC HEALTH RELEVANCE: Despite major advances in treatment strategies and patient outreach programs over the past two and a half decades, the prevention of HIV infection remains an extremely difficult task throughout the world. Our work will help establish why male circumcision is an effective means of preventing HIV sexual transmission and aid in the future development of other preventative strategies such as HIV vaccines.